Chemotherapy and radiation therapy continue to be the main approaches to therapeutic treatment of cancer, with surgery providing the means of physically excising the cancer. More recently, biological agents such as antibodies have been developed as anti-cancer therapies.
The application of many anti-cancer agents and radiation therapy has been based on the premise that the cell death caused by the treatment with these anti-cancer therapies will bring biological processes into play that result in the cancerous cells being ultimately destroyed.
One of these processes is apoptosis. Apoptosis is the complex cellular program of self destruction, triggered by a variety of stimuli that results in self destruction where dying cells shrink, condense and then fragment, releasing small membrane-bound apoptotic bodies that are normally engulfed by other cells such as phagocytes.
Conventional chemotherapeutic agents covalently bond with DNA to form adducts, thereby resulting in DNA damage, and triggering apoptosis. Traditional chemotherapeutic agents suffer from two major disadvantages: (i) they cause severe side effects, because they also affect healthy proliferating cells; and (ii) increased resistance to the agents by the cancerous cells. In this regard, cancer cells have the ability to develop resistance to the chemotherapeutic agents over time, and ultimately may develop multi-drug resistance.
Inhibition of apoptosis in drug resistant tumours not only affects the death-inducing activities of the drug, but also allows for the possibility of cells acquiring additional mutations following DNA damage. In principle, these mutagenised cells can become more malignant and even less sensitive to subsequent therapies, such that treatment of highly resistant tumours containing anti-apoptotic lesions may do more harm than good.
One of the hallmarks of cancer cells is that they evade apoptosis. Disruption of the apoptotic pathway has important effects on the clinical outcome of chemotherapy. In order for chemotherapeutic agents to be effective, cells must be capable of undergoing apoptosis. Apoptosis is therefore a vitally important phenomenon in cancer chemotherapy, because many anti-cancer drugs exert their initial antitumour effect against cancer cells by inducing apoptosis.
However, not only can some chemotherapeutic drugs inhibit apoptosis after a short period of time, but many tumours also have defective apoptotic pathways and as such are inherently more resistant to chemotherapy. Furthermore, although the rate of apoptosis is not necessarily high in tumour tissues, the induction of apoptosis is correlated with tumour response and clinical outcome in cancer patients.
One of the major obstacles to treatment of many types of cancer is the development or presence of resistance to chemotherapeutic agents, such as occurs in non-small cell lung cancer. For example, the development of cisplatin resistance is a major cause of treatment failure. Several mechanisms have been implicated in cisplatin resistance, one of which is altered expression of oncogenes (e.g. Bcl-2) that subsequently suppress apoptotic pathways and may also contribute to development of resistance.
Accordingly there is a need for agents that may be used in conjunction with anti-cancer therapies to enhance their activity against cancerous cells. The present invention relates to the use of steroid saponins to promote the activity of anti-cancer agents and anti-cancer treatments.
A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that the document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.